Effects of long-term hypergastrinemia on gastric mucosa

• Project/Area Number: 16K09293
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Nippon Medical School
• Principal Investigator: IWAKIRI katsuhiko 日本医科大学, 大学院医学研究科, 大学院教授 (50221099)
• Co-Investigator(Kenkyū-buntansha): 清水 章 日本医科大学, 大学院医学研究科, 大学院教授 (00256942) ; 辰口 篤志 日本医科大学, 医学部, 講師 (10350125) ; 野村 務 日本医科大学, 医学部, 准教授 (60287737)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 高ガストリン血症 / プロトンポンプ阻害薬(PPI) / カルチノイド腫瘍 / プロトンポンプ阻害薬（PPI) / プロトンポンプ阻害薬（PPI）

Outline of Final Research Achievements

There were no neuroendocrine tumor (NET) or gastric epithelial neoplasia cases observed among any of the 20 patients with hypergastrinemia throughout the PPI treatment longer than four years. Histologically, parietal cell protrusion was recognized in all patients. However, no morphological changes in ECL cells or neuroendocrine cells were observed, including linear and micronodular ECL cell hyperplasia. There was no relationship between serum gastrin levels and the number of chromogranin A, which is a marker of ECL cells, positive cells in the fundic gland area. Hypergastrinemia secondary to long-term PPI treatment proved not to be associated with ECL cell tumorigenesis including NET.

Academic Significance and Societal Importance of the Research Achievements

本研究で、PPI長期内服することで高ガストリン血症をきたしても神経内分泌腫瘍や胃癌の発生はみられず、病理組織学的にも有意な変化は認められなかった。したがってPPIを長期内服されている患者において、腫瘍発生のリスクが増加することはなく、安全に内服を継続することができることが示された。
この結果は、今後さらに増加すると予想される逆流性食道炎、非びらん性胃食道逆流症診療において重要な臨床的意義を有すると考える。

Research Products

• [Journal Article] Efficacy of on-demand therapy using 20-mg vonoprazon for non-erosive reflux disease (2019)
  • Author(s): Yoshimasa Hoshikawa, Noriyuki Kawami, Shintaro Hoshino, Tomohide Tanabe, Mariko Umezawa, Mitsuru Kaise, Katsuhiko Iwakiri
  • Journal Title: Esophagus Volume: 16 Issue: 2 Pages: 201-206
  • DOI: 10.1007/s10388-018-00654-9
  • Peer Reviewed
• [Journal Article] Efficacy of On-Demand Therapy Using 20-mg Vonoprazan for Mild Reflux Esophagitis. (2018)
  • Author(s): Umezawa M. · Kawami N. · Hoshino S. · Hoshikawa Y. · Koizumi E. · Takenouchi N. · Hanada Y. · Kaise M. · Iwakiri K.
  • Journal Title: Digestion Volume: 97 Issue: 4 Pages: 309-315
  • DOI: 10.1159/000485795
  • Peer Reviewed
• [Journal Article] Endoscopic diagnosis of hiatus hernia under deep inspiration is not consistent with esophageal manometric diagnosis. (2018)
  • Author(s): Hanada Y, Hoshino S, Hoshikawa Y, Takenouchi N, Umezawa M, Kawami N, Iwakiri K.
  • Journal Title: J Gastroenterol Volume: - Issue: 6 Pages: 712-717
  • DOI: 10.1007/s00535-017-1403-5
  • Peer Reviewed
• [Journal Article] Pathogenesis of Potassium-Competitive Acid Blocker-Resisitant Non-Erosive Reflux Disease (2018)
  • Author(s): Kawami N, Hoshino S, Hoshikawa Y, Takenouchi N, Umezawa M, Hanada Y, Kaise M, Iwakiri K
  • Journal Title: Digestion Volume: - Issue: 3 Pages: 194-200
  • DOI: 10.1159/000488530
  • Peer Reviewed
• [Journal Article] Treatment Strategy for Standard-Dose Proton Pump Inhibitor-Resistant Reflux Esophagitis (2017)
  • Author(s): Iwakiri K
  • Journal Title: Journal of Nippon Medical School Volume: 84 Issue: 5 Pages: 209-214
  • DOI: 10.1272/jnms.84.209
  • NAID: 130006206370
  • ISSN: 1345-4676, 1347-3409
  • Peer Reviewed / Open Access
• [Journal Article] Mechanisms underlying excessive esophageal acid exposure in patients with gastroesophageal reflux disease (2017)
  • Author(s): Iwakiri K, Hoshino S, Kawami N
  • Journal Title: Esophagus Volume: 14 Issue: 3 Pages: 221-228
  • DOI: 10.1007/s10388-017-0575-7
  • NAID: 40021255121
  • Peer Reviewed
• [Journal Article] Pathogenesis of Double-Dose Proton Pump Inhibitor-Resistant Non-Erosive Reflux Disease, and Mechanism of Reflux Symptoms and Gastric Acid Secretion-Suppressive Effect in the Presence or Absence of Helicobacter pylori Infection (2017)
  • Author(s): Kawami N, Takenouchi N, Umezawa M, Hoshino S, Hanada Y, Hoshikawa Y, Sano H, Hoshihara Y, Nomura T, Uchida E, Iwakiri K.
  • Journal Title: Digestion Volume: 95 Issue: 2 Pages: 140-145
  • DOI: 10.1159/000455834
  • Peer Reviewed
• [Journal Article] Efficacy of Vonoprazan for Proton Pump Inhibitor-Resistant Reflux Esophagitis (2017)
  • Author(s): Hoshino S, Kawami N, Takenouchi N, Umezawa M, Hanada Y, Hoshikawa Y, Kawagoe T, Sano H, Hoshihara Y, Nomura T, Iwakiri K
  • Journal Title: Digestion Volume: 95 Issue: 2 Pages: 156-161
  • DOI: 10.1159/000456072
  • Peer Reviewed
• [Journal Article] Effects of acotiamide on esophageal motility in healthy subjects: a randomized, double-blind, placebo-controlled crossover study (2017)
  • Author(s): Hoshino S, Takenouchi N, Hanada Y, Umezawa M, Sano H, Kawami K, Hoshikawa Y, Kawagoe T, Nomura T, Hoshihara Y, Iwakiri K
  • Journal Title: Esophagus Volume: 14 Issue: 2 Pages: 146-152
  • DOI: 10.1007/s10388-016-0559-z
  • NAID: 40021166226
  • Peer Reviewed
• [Presentation] 長期ガストリン血症の胃粘膜に及ぼす影響 (2019)
  • Author(s): 辰口 篤志、星野 慎太朗、川見 典之、岩切 勝彦
  • Organizer: 第15回日本消化管学会総会学術集会
• [Presentation] A Phase 3, Randomized, Double-Blind, Multicenter Study to Evaluate the Dose-Response Relationships of Acid-Inhibitory Effect of Vonoprazan (20mg, 40mg) in Patients With Proton Pump Inhibitor-Resistant Erosive Esophagitis (2016)
  • Author(s): Iwakiri K, Umegaki E, Hiramatsu N, Sakurai Y, Shiino M, Okamoto H, Nishimura A, Ashida K
  • Organizer: Digestive Disease Week (DDW) 2016
  • Place of Presentation: San Diego
  • Year and Date: 2016-05-21
  • Int'l Joint Research
• [Presentation] Efficacy of Vonoprazan on PPI-Resisitant Reflux Esophagitis (2016)
  • Author(s): Hanada Y, Hoshino S, Hoshikawa Y, Takenouchi N, Umezawa M, Kawami N, Hoshihara Y, Iwakiri K
  • Organizer: Digestive Disease Week (DDW) 2016
  • Place of Presentation: San Diego
  • Year and Date: 2016-05-21
  • Int'l Joint Research
• [Presentation] Circumferential Distribution of Mild Esophageｌ Mucosal Break (Los Angeles Classification Grades A and B) in the Lower Esophagus (2016)
  • Author(s): Kawami N, Yamada A, Hoshihara Y, Hanada Y, Hoshikawa Y, Takenouchi N, Hoshino S, Umezawa M, Aida J, Takubo K, Iwakiri K
  • Organizer: Digestive Disease Week (DDW) 2016
  • Place of Presentation: San Diego
  • Year and Date: 2016-05-21
  • Int'l Joint Research